Better management of fluid and volume control with better hemodialysis prescriptions.

1. AdvancingDialysis.org
Better Management of
Volume with Intensive Hemodialysis
STRIKING A BALANCE:
HYPERVOLEMIA AND HYPOVOLEMIA MANAGEMENT

2. AdvancingDialysis.org
Challenges of Managing Fluid
During and Between Standard Hemodialysis Sessions
• Constraint imposed by standard hemodialysis schedule:
‒ 3 sessions per week for a total of 11 treatment hours
‒ Allows three interdialytic gaps
• 2 gaps of approximately 48 hours each
• 1 gap of approximately 72 hours
• Fluid accumulates during these gaps, particularly in the extracellular space, putting
stress on the heart
• Presents challenges to interventional strategies given ultrafiltration protocols
‒ Set ultrafiltration rate to remove necessary volume to during set treatment time
‒ Remove as much volume as possible within a set ultrafiltration rate limit

3. AdvancingDialysis.org
Increased Risk of Sudden Cardiac Death1
• Decreased eGFR has been
suggested to cause endocardial
and diffuse myocardial fibrosis that
could increase the risk of life-
threatening ventricular arrhythmias
and sudden cardiac death (SCD)2
• Each 10 mL/min/1.73 m2 decline in
eGFR has been associated with an
11% increased risk of SCD1
General
population
1.5
CVD, GFR >60
3.8
CKD stage III, IV
7.3
CKD stage V,
non-dialysis
12.6
Dialysis
24.2
0 5 10 15 20 25 30
EVENTS PER 1000 PATIENT YEARS
RATES OF SUDDEN CARDIAC DEATH IN
SELECTED POPULATIONS1,3
1Pun, P.H. et al. Chronic kidney disease is associated with
increased risk of sudden cardiac death among patients with
coronary artery disease. Kidney International (2009) 76, 652–658.
2Mark PB, Johnston N, Groenning BA et al. Redefinition of uremic
cardiomyopathy by contrast-enhanced cardiac magnetic
resonance imaging. Kidney Int 2006; 69: 1839–1845.
3Hayashi M., Shimizu W., Albert C.M. The Spectrum of
Epidemiology Underlying Sudden Cardiac Death. Circulation
Research. 2015;116:1887-1906

4. AdvancingDialysis.org
Approximately 4 in 5 dialysis
patients have diagnoses of
diabetes, heart failure, or
cardiac arrhythmia.
CARDIAC
ARRHYTHMIA
HEART
FAILURE
DIABETES
PREVALENCE &
HAZARD RATIO
14%
HR = 3.2 5%
HR = 2.0
16%
HR = 5.0
5%
HR = 3.6
7%
HR = 2.5
4%
HR = 1.9
27%
HR = 1.7
21%
HR = 1.0
Any 1 of 3 conditions:
1.7–2.0 times higher
risk of CV death
Any 2 of 3 conditions:
2.5–3.6 times higher risk of
CV death
All 3 conditions:
5.0 times higher risk
Dialysis is Associated with Pressure,
Volume and Heart-related Morbidity1
1Special data analyses: 2016 USRDS ESRD Database and Medicare claims data.

5. AdvancingDialysis.org
Hypertension, Left Ventricular
Hypertrophy and Heart Failure
FATAL FLAW OF STANDARD HEMODIALYSIS

6. AdvancingDialysis.org
Changes in Volume Status Over
1-WEEK DURING STANDARD HEMODIALYSIS
Volume status over 1-week
during thrice weekly dialysis.
The oscillation of fluid volume
status reflects IDWG and
dialytic ultrafiltration.
Dry weight is approximated by
the postdialysis weight which,
however, is often not the
optimal fluid volume status.1
1Ohashi Y et al. Dry weight targeting: The art and science of conventional hemodialysis. Seminars in Dialysis,
Volume: 31, Issue: 6, Pages: 551-556.

7. AdvancingDialysis.org
Unmet Need in the Causal Path of
Heart Disease in Dialysis
1Rocco MV, Burkart JM. Prevalence of missed treatments and early sign-offs in hemodialysis patients. J Am
Soc Nephrol. 1993 Nov;4(5):1178-83.
Fluid
Overload
Uncontrolled
Hypertension
Left Ventricular
Hypertrophy
Heart Failure
Hospitalization
and Death
Early Sign-Offs
and No-Shows1
High
Ultrafiltration
Rate
Intradialytic
Hypotension
Cramping,
Dizziness,
Nausea, etc.
Long Post-
Dialysis
Recovery
Time
Poor HRQoL
Cardiac &
organ system
Stunning
Limits Use of
Cardioprotective
Medicines
Driven by
interdialytic
volume issues

8. AdvancingDialysis.org
Normal Systolic Pressure
RVSP
Elevated Right Heart Pressures
PATTERNS IN PATIENTS UNDERGOING STANDARD HEMODIALYSIS1
1Kjellström B, Braunschweig F, Löfberg E, Fux T, Grandjean PA, Linde C. Changesin right ventricular
pressures between hemodialysis sessions recorded by animplantable hemodynamic monitor. Am J Cardiol.
2009 Jan 1;103(1):119-23
Volume loading creates markedly
abnormal cardiac pressure.
The loading between treatments
create high wall stresses, LVH, and
systolic and diastolic dysfunction.

9. AdvancingDialysis.org
Clinically Significant Arrhythmias
PATTERNS IN PATIENTS UNDERGOING STANDARD HEMODIALYSIS1
• Highest during the first
hemodialysis session of the week
• 2nd highest during the final 12
hours of the long interdialytic gap
• 3rd highest during the 12 hours
immediately following the first
session of the week
• Meaningfully elevated during the
final 12 hours of each of the short
interdialytic gaps
1Roy-Chaudhury, P., et al. Primary outcomes of the Monitoring in Dialysis Study
indicate that clinically significant arrhythmias are common in hemodialysis patients
and related to dialytic cycle. Kidney Int. 2018;93:941–951.

10. AdvancingDialysis.org
Long Interdialytic Interval is Problematic
HOSPITALIZATIONS AND MORTALITY AFTER THE 2-DAY “KILLER GAP”
• The long interdialytic interval, commonly
referred to as the 2-day “Killer Gap,” is a
time of heightened risk of mortality and
morbidity with conventional hemodialysis1
• Rates of death and cardiovascular
hospitalization were 23% and 124%
higher after the gap, respectively, than on
other days1
FIGURE:
Rates of death and cardiovascular hospitalization on the day
after the 2-day gap in dialysis treatment and on all others
days.2
1Foley, R. N., Gilbertson, D. T., Murray, T., & Collins, A. J. (2011). Long interdialytic interval and mortality among patients
receiving hemodialysis. New England Journal of Medicine, 365(12), 1099-1107. 2McCullough PA et al. Intensive
Hemodialysis, Left Ventricular Hypertrophy, and Cardiovascular Disease. Vol 68 (5):1;S5-S14.

11. AdvancingDialysis.org
Unmet Need in the Causal Path
of Heart Disease in Dialysis
1Rocco MV, Burkart JM. Prevalence of missed treatments and early sign-offs in hemodialysis patients. J Am
Soc Nephrol. 1993 Nov;4(5):1178-83.
Fluid
Overload
Uncontrolled
Hypertension
Left Ventricular
Hypertrophy
Heart Failure
Hospitalization
and Death
Early Sign-Offs
and No-Shows1
High
Ultrafiltration
Rate
Intradialytic
Hypotension
Cramping,
Dizziness,
Nausea, etc.
Long Post-
Dialysis
Recovery
Time
Poor HRQoL
Cardiac &
organ system
Stunning
Limits Use of
Cardioprotective
Medicines
Driven by
intradialytic
volume issues

12. AdvancingDialysis.org
Dialysis Induced Stress on the Heart:
VARIES BY MODALITY
VOLUME
OVERLOAD
PRESSURE
OVERLOAD
INTRADIALYTIC
MYOCARDIAL
STUNNING
CARDIOVASCULAR
RELATED DEATH
CARDIOMYOPATHY

13. AdvancingDialysis.org
- ↑ 3%
↑ 9%
↑ 15%
↑ 23%
↑ 43%
80%
90%
100%
110%
120%
130%
140%
150%
160%
<6 6 to 8 8 to 10 10 to 12 12 to 14 >14
Ultrafiltration Rates over 8mL/kg/h
ASSOCIATED RISK OF DEATH1
1Assimon, M.M. et al. Ultrafiltration Rate and Mortality in Maintenance Hemodialysis Patients. Am J Kidney Dis.
2016;68(6):911-922.
Rate of fluid removal from the patient – mL/kg/h
Increased
Risk of Death
118,394 STANDARD
HEMODIALYSIS PATIENTS
2008-2012

14. AdvancingDialysis.org
Mitigating Aggressive Ultrafiltration Rates1
• UF = ultrafiltration
• IDWG = interdialytic
weight gain
• TT= treatment time
(dialysis session length)
UF rate (mL/kg/h) =
TT (h)
IDWG (mL)
Post-weight
(kg)
Extend dialysis time
↓ Weight gain
↓ UF volume
1Figure 1: Assimon MM, Flythe JE. Rapid ultrafiltration rates and outcomes among hemodialysis patients:
re-examining the evidence base. Curr Opin Nephrol Hypertens. 2015 Nov; 24(6): 525–530.

15. AdvancingDialysis.org
No Major Changes in Prescription or Dose
2010-2017 HEMODIALYSIS TREATMENT CHARACTERISTICS1
1Arbor Research Collaborative for Health. The DOPPS Practice Monitor. http://www.dopps.org/DPM/.
Accessed April, 23, 2019.
180
190
200
210
220
230
240
Session Length
90%
92%
94%
96%
98%
100%
% Treatments 3/week
1.30
1.40
1.50
1.60
1.70
1.80
Single-pool Kt/V

16. AdvancingDialysis.org
No Significant Change in Patient Population
2010-2017 HEMODIALYSIS PATIENT CHARACTERISTICS1
1Arbor Research Collaborative for Health. The DOPPS Practice Monitor. http://www.dopps.org/DPM/.
Accessed April, 23, 2019.
50
55
60
65
70
75
Age
19
24
29
34
39
Body Mass Index
0
1
2
3
4
5
Years on dialysis

17. AdvancingDialysis.org
Significant Reduction in
Hemodialysis Ultrafiltration Rates1
1Arbor Research Collaborative for Health. The DOPPS Practice Monitor. http://www.dopps.org/DPM/.
Accessed April, 23, 2019.
2Assimon MM, Flythe JE. Rapid ultrafiltration rates and outcomes among hemodialysis patients: re-examining
the evidence base. Curr Opin Nephrol Hypertens. 2015 Nov; 24(6): 525–530.
9.3
9.0 9.0
9.3 9.2
8.8
8.6
8.9
8.4
8.2
8.3
7.9
8.2 8.2 8.2 8.2
8.0
7.8
8.0
7.8 7.9 7.9
7.8
2010 2011 2012 2013 2014 2015 2016 2017
Mean Ultrafiltration Rate
(mL/kg/h)
POTENTIAL HARM SEEMINGLY
ACKNOWLEDGED2
15% FROM 2010 - 2017

18. AdvancingDialysis.org
R² = 0.7842
7.2
7.7
8.2
8.7
9.2
2.6 2.7 2.8 2.9 3.0 3.1 3.2 3.3
Median ultrafiltration rate
(mL/kg/h)
Median intradialytic weight loss (%)
Arbor Research Collaborative for Health. The DOPPS Practice Monitor. http://www.dopps.org/DPM/.
Accessed April, 23, 2019.
Should a Decrease in Intradialytic Weight
Loss be Cause for Concern? 2010
8.9 ML/KG/H ULTRAFILTRATION RATE
3.1% INTRADIALYTIC
WEIGHT LOSS
2017
7.6 ML/KG/H ULTRAFILTRATION RATE
2.7%
↓14% INTRADIALYTIC
WEIGHT LOSS

19. AdvancingDialysis.org
Sudden Upturn in Rate of
Cardiovascular Hospitalizations
2018 USRDS Annual Data Report: Adjusted all-cause & cause-specific hospitalization rates for ESRD patients,
by treatment modality, 2007-2016. Vol 2; Chapter 4.
0.56
0.53 0.53
0.51
0.49
0.46
0.43
0.41 0.42
0.45
2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Cardiovascular-related Hospitalization Rate:
Hemodialysis Patients
7% INCREASED RATE
CARDIOVASCULAR HOSPITALIZATIONS
2015-2016

20. AdvancingDialysis.org
Indications of Poor Fluid Management
BETWEEN, DURING AND AFTER STANDARD HEMODIALYSIS
Diagram concept courtesy of Dr. Jennifer Flythe, Wake Forest University
Hypovolemic
Primary intradialytic driver 
aggressive ultrafiltration rates exhibit
• Hemodynamic instability
• End-organ ischemia
• Cramping, nausea
• Thirst, fatigue
Hypervolemic
Primary interdialytic driver 
fluid expansion and overload exhibits
• Hypertension
• Ventricular hypertrophy
• Heart failure, arrhythmia
• Dyspnea

21. AdvancingDialysis.org
Chronic Fluid Overload and Mortality Risk:
INCREASED MORTALITY RISK ≥1KG OVER DRY WEIGHT
1Flythe JE, Assimon MM, Overman RA. Target weight achievement and ultrafiltration rate thresholds: potential
patient implications. BMC Nephrol. 2017; 18: 185.
2Zocalli C et al. Chronic Fluid Overload and Mortality in ESRD. J Am Soc Nephrol. 2017 Aug; 28(8): 2491–2497.
3Dekker MJE et al. Impact of fluid status and inflammation and their interaction on survival: a study in an international
hemodialysis patient cohort. Kidney International (2017) 91, 1214–1223.
Flythe1
• 30-day follow-up
• ≥50 percent of
treatments leaving
patients >1kg “heavy”
•  35%
increased risk
for mortality
Zocalli2
• 1-year follow-up
• Average 1.6kg
removed
•~1Kg “heavy”
•  62%
increased risk
for mortality
Dekker3
• 1-year follow-up
• 1.1 L to 2.5 L –
considered moderate
fluid overload
•  64%
increased risk of
death

22. AdvancingDialysis.org
Addressing Consistent Volume Control
INCREASED TREATMENT TIME AND FREQUENCY
*See references on slides 28-30
Clinical Considerations for Number of
Hemodialysis Treatments per Week:*
3 Tx 3.5 – 4 Tx 5+ Tx
(“Daily”)
5+ Tx
(“Nocturnal”)
• Longer hemodialysis
treatment time (ex.
nocturnal treatments)
has improved mortality
in observational studies1
• Could mitigate the 2-day
killer gap2
• Possibility to decrease
UFR with 2-3 additional
hours of time per
treatment3,4
• Improved BP control &
survival1,4-8
• Reduced LVH &
cardiovascular
hospitalizations4,7,8,10
• Reduced UFR, recovery
time & hypotensive
episodes3-5,10-15
• Improvements in sleep
quality, RLS &
HRQoL5,16-18
• Limits volume loading
between treatments
Benefits from 5+ days per
week plus:
• Improved sleep and
obstructive sleep
apnea14,17
• Best dialytic PO4
control4,20,21
• Increased reduction in
post dialysis recovery
time15

23. AdvancingDialysis.org
Frequency and Duration Positively
Addresses Aggressive Ultrafiltration Rates1
1Analysis of NxStage Nx2me Flowsheets During Patient-Weeks with ≥4 Prescribed Treatments
48.9%
69.7%
86.2%
95.5%
<6 ML/KG/H <8 ML/KG/H <10 ML/KG/H <13 ML/KG/H
Diurnal Treatments
by Ultrafiltration Rate Category
97.7% 99.5% 99.8% 100.0%
<6 ML/KG/H <8 ML/KG/H <10 ML/KG/H <13 ML/KG/H
Nocturnal Treatments
by Ultrafiltration Rate Category

24. AdvancingDialysis.org
1The FHN Trial Group. In-Center Hemodialysis Six
Times per Week versus Three Times per Week. The
New England Journal of Medicine. 010:363;2287-2300.
2Weinhandl ED et al. Hospitalization in Daily Home
Hemodialysis and Matched Thrice-Weekly In-Center
Hemodialysis Patients. Am J Kidney Dis. 65(1):98-108.
More frequent
hemodialysis
associated with
improvements in
several
cardiovascular
markers and related
hospitalizations1,2
Likely due to improved
control of extracellular
volume excess.2
Left ventricular mass
Adjusted mean reduction of
16.4±2.9 g versus 2.6±3.2
(P<0.001)
12%
REDUCTION
FHN RANDOMIZED CLINICAL TRIAL FINDINGS:
Hypotensive episodes
10.9% vs. 13.6% of monitored
sessions with at least one
episode, (P=0.04)
20%
FEWER
Systolic blood pressure
Adjusted mean SPB decrease
9.7±18.2 mm Hg versus 0.9±16.2
mm Hg (P<0.001)
7%
DECREASE
Antihypertensive agents
Change from baseline agents
decreased 0.87±1.85 versus
−0.23±1.35 (P< .001)
36%
LESS

25. AdvancingDialysis.org
Summarized Findings by Eric Weinhandl, PhD, MS
ADJUNCT ASSISTANT PROFESSOR
UNIVERSITY OF MINNESOTA COLLEGE OF PHARMACY
CLINICAL EPIDEMIOLOGIST AND STATISTICIAN
NXSTAGE MEDICAL, INC.
Better Management of Volume with Intensive Hemodialysis:
• Not achieving dry weight during hemodialysis sessions contributes to persistent fluid
overload, uncontrolled hypertension and left ventricular hypertrophy progression.1
• Controlling the high prevalence of fluid overload and the use of aggressive ultrafiltration
rates are widely considered unmet clinical needs in conventional hemodialysis2
• Restricting fluid intake is not a viable strategy given 1/3 – 1/2 of patients are not adherent2
• Absent effective fluid intake strategies, frequency and time can positively address volume
loading between hemodialysis sessions and ultrafiltration intensity by increasing treatment
frequency and cumulative treatment hours per week3
1Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli GF. Braunwald’s Heart Disease: A Textbook of Cardiovascular
Medicine. 11th ed. Elsevier; 2018.
2Rocco MV, Burkart JM. Prevalence of missed treatments and early sign-offs in hemodialysis patients. J Am Soc Nephrol.
1993 Nov;4(5):1178-83.
3Raimann, J.G., et al. The Effect of Increased Frequency of Hemodialysis on Volume-Related Outcomes: A Secondary
Analysis of the Frequent Hemodialysis Network Trials. Blood Purif 2016;41:277–286.

26. AdvancingDialysis.org
About this presentation
This presentation is one in an ongoing series focused on recent articles, clinical findings or
guidelines related to issues affecting dialysis patients.
AdvancingDialysis.org is dedicated to providing clinicians and patients with better access to
and more awareness of the reported clinical benefits and improved quality of life made
possible with home dialysis, including solo and nocturnal therapy schedules.
For more information, visit AdvancingDialysis.org
AdvancingDialysis.org is a project of NxStage Medical, Inc.

27. AdvancingDialysis.org
Risks and Responsibilities
Not everyone will experience the reported benefits of home and more frequent
hemodialysis. All forms of hemodialysis involve some risks. When vascular access is
exposed to more frequent use, infection of the site, and other access related complications
may also be potential risks.
Certain risks associated with hemodialysis treatment are increased when performing solo
home hemodialysis because no one is present to help the patient respond to health
emergencies.
Certain risks associated with hemodialysis treatment are increased when performing
nocturnal therapy due to the length of treatment time and because the patient and care
partner are sleeping.

28. AdvancingDialysis.org
Addressing Consistent Volume Control
REFERENCES
1Rivara MB et al. Extended-hours hemodialysis is associated with lower mortality risk in patients with end-stage renal
disease. Kidney Int. 2016 Dec;90(6):1312-1320.
2Foley, R. N., Gilbertson, D. T., Murray, T., Collins, A. J. Long interdialytic interval and mortality among patients receiving
hemodialysis. NEJM. 2011;365(12):1099-1107.
3Raimann, J.G., et al. The Effect of Increased Frequency of Hemodialysis on Volume-Related Outcomes: A Secondary
Analysis of the Frequent Hemodialysis Network Trials. Blood Purif 2016;41:277–286.
4FHN Trial Group, Chertow, G.M., Levin, N.W., Beck, G.J. et al. In-center hemodialysis six times per week versus three times
per week. N Engl J Med. 2010; 363: 2287–2300.
5Morfin, J.A., Fluck, R.J., Weinhandl, E.D., Kansal, S., McCullough, P.A., and Komenda, P. Intensive hemodialysis and
treatment complications and tolerability. Am J Kidney Dis. 2016; 68: S43–S50.
6Bakris, G.L., Burkart, J.M., Weinhandl, E.D., McCullough, P.A., and Kraus, M.A. Intensive hemodialysis, blood pressure, and
antihypertensive medication use. Am J Kidney Dis. 2016; 68: S15–S23.
7Weinhandl ED, Gilbertson DT, Collins AJ. Mortality, Hospitalization, and Technique Failure in Daily Home Hemodialysis and
Matched Peritoneal Dialysis Patients: A Matched Cohort Study. Am J Kidney Dis. 2016;67(1):98-110.
8Weinhandl, E.D., Liu, J., Gilbertson, D.T., Arneson, T.J., Collins, A.J. Survival in daily home hemodialysis and matched thrice-
weekly in-center hemodialysis patients. J Am Soc Nephrol. 2012;23:895–904.
9Chan, C.T., Greene, T., Chertow, G.M. et al. Determinants of left ventricular mass in patients on hemodialysis: Frequent
Hemodialysis Network (FHN) Trials. Circ Cardiovasc Imaging. 2012; 5: 251–261.

29. AdvancingDialysis.org
10McCullough, P.A., Chan, C.T., Weinhandl, E.D., Burkart, J.M., and Bakris, G.L. Intensive hemodialysis, left ventricular
hypertrophy, and cardiovascular disease. Am J Kidney Dis. 2016; 68: S5–S14.
11Weinhandl, Collins, Kraus. Ultrafiltration Rates with More Frequent Home Hemodialysis. Oral Presentation. 2017 ADC.
12Stefánsson, B.V., Brunelli, S.M., Cabrera, C. et al. Intradialytic hypotension and risk of cardiovascular disease. Clin J Am
Soc Nephrol. 2014; 9: 2124–2132.
13Jefferies, H.J., et al. Frequent Hemodialysis Schedules Are Associated with Reduced Levels of Dialysis-induced Cardiac
Injury (Myocardial Stunning). Clin J Am Soc Nephrol. 2011 June; 6(6): 1326–1332.
14Jaber BL, Lee Y, Collins AJ, et al. Effect of daily hemodialysis on depressive symptoms and postdialysis recovery time:
interim report from the FREEDOM (Following Rehabilitation, Economics and Everyday-Dialysis Outcome Measurements)
Study. Am J Kidney Dis. 2010;56(3):531-539.
15Lindsay RM, Heidenheim PA, Nesrallah G, Garg AX, Suri R, Daily Hemodialysis Study Group London Health Sciences
Centre. Minutes to recovery after a hemodialysis session: a simple health-related quality of life question that is reliable, valid,
and sensitive to change. CJASN. 2006;1(5):952-959.
16Jaber BL, et al. Impact of Short Daily Hemodialysis on Restless Legs Symptoms and Sleep Disturbances. CJASN May 2011
vol. 6 no. 5 1049-1056.
17Finkelstien FO, et al. At-home short daily hemodialysis improves the long-term health-related quality of life. Kidney
International (2012) 82, 561–569.
18Kraus, Michael A. et al. Intensive Hemodialysis and Health-Related Quality of Life. Am J of Kidney Dis. 2016;68:S33-S42.
Addressing Consistent Volume Control
REFERENCES

30. AdvancingDialysis.org
19Hanley, P.J., Pierratos, A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal
hemodialysis. N Engl J Med: 2001; Vol. 344, No. 2.
20Daugirdas JT, Chertow GM, Larive B, et al. Effects of frequent hemodialysis on measures of CKD mineral and bone
disorder. JASN. 2012;23(4):727-738.
21Copland, M. et al. Intensive Hemodialysis, Mineral and Bone Disorder, and Phosphate Binder Use. Am J Kid D: 2016;
Volume 68, Issue 5, Supplement 1, Pages S24–S32.
Addressing Consistent Volume Control
REFERENCES

31. AdvancingDialysis.org
www.AdvancingDialysis.org
© 2019 NxStage Medical, Inc.